Several non-receptor tyrosine kinases (nRTK) are highly expressed in the brain and are pivotal for brain functions and some mental diseases. Among brain-enriched nRTKs, Fyn draws the most attention. Recently, we found that Fyn directly binds to metabotropic glutamate receptor 5 (mGluR5), which enables Fyn to phosphorylate mGluR5 at a tyrosine site in the intracellular C-terminus (CT). These findings for the first time reveal mGluR5 as a direct substrate of Fyn. Encouraged by this new discovery, we propose this renewal application to further study the Fyn regulation of mGluR5 and to define roles of Fyn and mGluR1/5 in the pathogenesis and symptomology of a common mental illness. Our hypothesis is that Fyn binds and phosphorylates mGluR1/5 to control receptor function and promote depression-like behaviors. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo, as appropriate, in the following four inter-supportive Aims. Aim will characterize fundamental kinase-substrate biochemistry between Fyn and mGluR1/5 in vitro. Aim II will define the regulation of Fyn-mGluR1/5 interactions and tyrosine phosphorylation of mGluR1/5 by changing dopamine inputs in striatal neurons in vivo. Aim III will explore functional roles of Fyn-mediated phosphorylation in the modulation of trafficking and subcellular expression of mGluR1/5 and the efficacy of receptor signaling in striatal neurons. Aim IV will firs monitor neuroadaptations of striatal Fyn-mGluR1/5 interactions and mGluR1/5 phosphorylation in response to prolonged social isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood animals. Aim IV will then clarify the functional role of Fyn-mGluR1/5 interactions in isolation-induced depression-like behaviors. Results achieved here will conceptually advance our current understanding of the phosphorylation-dependent regulation of glutamate receptor signaling. They will also ultimately contribute to the development of novel pharmacotherapies, by targeting an nRTK (Fyn) and mGluR1/5, for the treatment of some core symptoms of depression.